CN117510400A - Preparation method of 6-bromo-2-chloro-3-nitropyridine - Google Patents
Preparation method of 6-bromo-2-chloro-3-nitropyridine Download PDFInfo
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- CN117510400A CN117510400A CN202311617234.6A CN202311617234A CN117510400A CN 117510400 A CN117510400 A CN 117510400A CN 202311617234 A CN202311617234 A CN 202311617234A CN 117510400 A CN117510400 A CN 117510400A
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- nitropyridine
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- ZOETZKWSHCVJQA-UHFFFAOYSA-N 6-bromo-2-chloro-3-nitropyridine Chemical compound [O-][N+](=O)C1=CC=C(Br)N=C1Cl ZOETZKWSHCVJQA-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- YRXZIHANXVKUHP-UHFFFAOYSA-N 6-bromo-3-nitropyridin-2-amine Chemical compound NC1=NC(Br)=CC=C1[N+]([O-])=O YRXZIHANXVKUHP-UHFFFAOYSA-N 0.000 claims abstract description 26
- -1 6-bromo-2-hydroxy-3-nitropyridine Chemical compound 0.000 claims abstract description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 15
- 238000001308 synthesis method Methods 0.000 claims abstract description 13
- WERABQRUGJIMKQ-UHFFFAOYSA-N 6-chloro-3-nitropyridin-2-amine Chemical compound NC1=NC(Cl)=CC=C1[N+]([O-])=O WERABQRUGJIMKQ-UHFFFAOYSA-N 0.000 claims abstract description 11
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000012320 chlorinating reagent Substances 0.000 claims abstract description 8
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- 239000000243 solution Substances 0.000 claims description 30
- 238000003756 stirring Methods 0.000 claims description 27
- 239000007787 solid Substances 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 18
- 239000005457 ice water Substances 0.000 claims description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 10
- 235000010288 sodium nitrite Nutrition 0.000 claims description 9
- MNZMECMQTYGSOI-UHFFFAOYSA-N acetic acid;hydron;bromide Chemical compound Br.CC(O)=O MNZMECMQTYGSOI-UHFFFAOYSA-N 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 239000012074 organic phase Substances 0.000 claims description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 7
- 239000002244 precipitate Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 239000003208 petroleum Substances 0.000 claims description 5
- 230000001376 precipitating effect Effects 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 238000001704 evaporation Methods 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 4
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 4
- 238000004321 preservation Methods 0.000 claims description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims description 2
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims description 2
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 11
- 230000008901 benefit Effects 0.000 abstract description 7
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract 1
- 230000001276 controlling effect Effects 0.000 description 17
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- JULQLOHNPMMKTH-UHFFFAOYSA-N 2-bromo-6-nitropyridine Chemical compound [O-][N+](=O)C1=CC=CC(Br)=N1 JULQLOHNPMMKTH-UHFFFAOYSA-N 0.000 description 1
- BPYHGTCRXDWOIQ-UHFFFAOYSA-N 3-nitropyridin-2-amine Chemical compound NC1=NC=CC=C1[N+]([O-])=O BPYHGTCRXDWOIQ-UHFFFAOYSA-N 0.000 description 1
- 102100025101 GATA-type zinc finger protein 1 Human genes 0.000 description 1
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 1
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention provides a synthesis method of 6-bromo-2-chloro-3-nitropyridine, and relates to the technical field of organic synthesis. The invention obtains 2-amino-3-nitro-6-bromopyridine through the reaction of 2-amino-3-nitro-6-chloropyridine and acetic acid solution of hydrogen bromide, diazotizes the pyridine to obtain 6-bromo-2-hydroxy-3-nitropyridine, and then reacts the 6-bromo-2-hydroxy-3-nitropyridine with a chlorinating agent to obtain 6-bromo-2-chloro-3-nitropyridine. The synthesis method of 6-bromo-2-chloro-3-nitropyridine provided by the invention has the advantages of easily available raw materials, low price, mild reaction conditions, simple process, higher economic benefit and suitability for large-scale production, can solve the current situation that the price of 6-bromo-2-chloro-3-nitropyridine is high, and plays a positive role in popularization of downstream products of 6-bromo-2-chloro-3-nitropyridine.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 6-bromo-2-chloro-3-nitropyridine.
Background
The 6-bromo-2-chloro-3-nitropyridine is used as a fine chemical raw material and has wide application in medical intermediates and the like. In patent WO2022042691A1, 6-bromo-2-chloro-3-nitropyridine is reported to be a key intermediate for synthesizing GLP-1 agonists, and as reported in patent CN109369641A, 6-bromo-2-chloro-3-nitropyridine is reported to be an important intermediate for synthesizing organic electroluminescent devices.
However, the synthesis method of 6-bromo-2-chloro-3-nitropyridine has not been reported so far, which results in higher price, and the price of 6-bromo-2-chloro-3-nitropyridine is high, which increases the cost burden for the popularization and application of downstream products.
Therefore, development of a synthesis method of 6-bromo-2-chloro-3-nitropyridine which is low in price, mild in reaction condition, simple in process, high in economic benefit and suitable for large-scale production is needed, the current situation that the price is high is solved, and the method plays a positive role in popularization of downstream products.
Disclosure of Invention
In order to overcome the defects, the invention provides a synthesis method of 6-bromo-2-chloro-3-nitropyridine, which comprises the steps of reacting 2-amino-3-nitro-6-chloropyridine with acetic acid solution of hydrogen bromide to obtain 2-amino-3-nitro-6-bromopyridine, diazotizing the 2-amino-3-nitropyridine to obtain 6-bromo-2-hydroxy-3-nitropyridine, and reacting the 6-bromo-2-hydroxy-3-nitropyridine with a chlorinating agent to obtain 6-bromo-2-chloro-3-nitropyridine. The synthesis method of 6-bromo-2-chloro-3-nitropyridine provided by the invention has the advantages of easily available raw materials, low price, mild reaction conditions, simple process, higher economic benefit and suitability for large-scale production, can solve the current situation that the price of 6-bromo-2-chloro-3-nitropyridine is high, and plays a positive role in popularization of downstream products of 6-bromo-2-chloro-3-nitropyridine.
The technical scheme of the invention comprises the following steps:
in one aspect, the invention provides a synthesis method of 6-bromo-2-chloro-3-nitropyridine, which has the technical scheme as follows:
the synthesis method comprises the following steps:
(1) 2-amino-3-nitro-6-chloropyridine reacts with hydrobromic acid acetic acid solution to obtain 2-amino-3-nitro-6-bromopyridine;
(2) Diazotizing 2-amino-3-nitro-6-bromopyridine to obtain 6-bromo-2-hydroxy-3-nitropyridine;
(3) And reacting the 6-bromo-2-hydroxy-3-nitropyridine with a chlorinating agent to obtain 6-bromo-2-chloro-3-nitropyridine.
Specifically, the step (1) is as follows:
adding 2-amino-3-nitro-6-chloropyridine into hydrobromic acid acetic acid solution, heating until T1 is completely reacted under heat preservation, evaporating the solution under reduced pressure, pouring the residue into ice water, adjusting pH, controlling the temperature to be T2, forming precipitate, filtering, washing with water, and drying to obtain 2-amino-3-nitro-6-bromopyridine;
or adding 2-amino-3-nitro-6-chloropyridine into hydrobromic acid acetic acid solution, heating until T1 is completely reacted under heat preservation, decompressing and steaming out the solution, pouring into ice water, adjusting pH, controlling the temperature at T2, filtering, washing with water, drying, and recrystallizing to obtain 2-amino-3-nitro-6-bromopyridine;
further specifically, the hydrobromic acid acetic acid solution in the step (1) is a 30% hydrobromic acid acetic acid solution.
Further specifically, the temperature of T1 in the step (1) is 30-150 ℃.
Preferably, the temperature of T1 in step (1) is 90-120 ℃.
Further preferably, the temperature of T1 in step (1) is 90-100deg.C, 100-110deg.C, 110-120deg.C.
Further specifically, the temperature of T2 in the step (1) is 0-30 ℃.
Preferably, the temperature of T2 in step (1) is 5-15 ℃.
Further preferably, the temperature of T2 in step (1) is 5-10deg.C, 10-15deg.C.
Further specifically, the reaction described in step (1) is complete, which is detected by HPLC.
Further specifically, the pH regulator used in the step (1) includes ethylenediamine, ethanolamine, ammonia water, sodium hydroxide, potassium hydroxide, and saturated aqueous solution of sodium bicarbonate.
Preferably, the pH regulator used for regulating the pH in the step (1) is ammonia water.
Further specifically, the pH of step (1) is 7 to 9.
Preferably, the pH in step (1) is 8.
More specifically, the drying in the step (1) is vacuum drying, and the temperature is 50-60 ℃.
Preferably, the vacuum drying temperature in the step (1) is 55 ℃.
Specifically, the step (2) is as follows: adding concentrated sulfuric acid into a reaction bottle, cooling to 5 ℃, adding 2-amino-3-nitro-6-bromopyridine obtained in the step (1), controlling the temperature to be not higher than 15 ℃, adding sodium nitrite aqueous solution when the temperature is reduced to 0 ℃, controlling the temperature to be within the range of T3, dripping the solution to be completely stirred at normal temperature overnight, completely reacting, pouring the reaction solution into ice water, controlling the temperature to be not higher than 30 ℃, precipitating solid under stirring, filtering,
washing with water and drying to obtain 6-bromo-2-hydroxy-3-nitropyridine.
More specifically, the mass concentration of the added concentrated sulfuric acid in the step (2) is 95%.
Further specifically, the temperature of T3 in the step (2) is-10-40 ℃.
Preferably, the temperature of T3 in step (2) is 0-15 ℃.
Further preferably, the temperature of T3 in step (2) is 0 ℃ to 5 ℃,5 ℃ to 10 ℃,10 ℃ to 15 ℃.
Further specifically, the molar ratio of the 2-amino-3-nitro-6-bromopyridine and sodium nitrite in the step (2) is 1:1-5.
Preferably, the molar ratio of the 2-amino-3-nitro-6-bromopyridine and sodium nitrite in the step (2) is 1:1-3.
Further preferably, the molar ratio of 2-amino-3-nitro-6-bromopyridine and sodium nitrite in step (2) is 1: 1. 1: 2. 1:3.
specifically, the step (3) is to add a solvent into a reaction bottle, add the 6-bromo-2-hydroxy-3-nitropyridine obtained in the step (2) under stirring, cool the ice salt bath to 0 ℃, add a chloridizing reagent under stirring, control the temperature within T4 range, keep the temperature to react completely, pour the reaction liquid into ice water, stir, adjust the pH, extract and combine organic phases, wash, dry, decolorize, filter, rinse, concentrate the organic phases to a small volume, precipitate solids, add petroleum ether, cool to 0-5 ℃ under stirring, filter, and dry to obtain the 6-bromo-2-chloro-3-nitropyridine.
Further specifically, the temperature of T4 in the step (3) is-10-40 ℃.
Preferably, the temperature of T4 in step (3) is 0-5 ℃.
More specifically, the solvent in the step (3) comprises ethyl acetate, 1, 4-dioxane, acetonitrile, N-dimethylformamide and toluene.
Preferably, the solvent in the step (3) is acetonitrile or toluene.
Further specifically, the chlorinating agent in the step (3) comprises phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, bis (trichloromethyl) carbonate and trichloromethyl chloroformate.
Preferably, the chlorinating agent in the step (3) is phosphorus trichloride, phosphorus oxychloride or phosphorus pentachloride.
More specifically, the pH regulator used in the step (3) comprises ethylenediamine, ethanolamine, ammonia water, sodium hydroxide, potassium hydroxide and sodium bicarbonate saturated aqueous solution.
Preferably, the pH adjuster used in the step (3) is a saturated aqueous solution of sodium bicarbonate.
Further specifically, the pH of the solution obtained in the step (3) is 6 to 9.
Preferably, the pH in step (3) is 7-8.
More specifically, the reaction in step (3) is complete, which is detected by TLC.
Further specifically, the solvent used for the extraction in step (2) is ethyl acetate.
More specifically, the drying in the step (3) is drying by adding anhydrous sodium sulfate.
More specifically, the decoloring in the step (3) is decoloring by adding activated carbon.
Further specifically, the leaching in the step (3) is ethyl acetate leaching.
In another aspect, the present invention provides the use of the above synthetic method, including the use in the preparation of 6-bromo-2-chloro-3-nitropyridine or an analogue thereof, and a pharmaceutically acceptable carrier and/or excipient.
In particular, the analogue is a derivative of 6-bromo-2-chloro-3-nitropyridine, a pharmaceutically acceptable salt thereof, a tautomer thereof and/or a stereoisomer thereof.
The invention has the technical effects that:
(1) The invention provides a synthesis method of 6-bromo-2-chloro-3-nitropyridine, which has the advantages of easily available raw materials, low price, mild reaction conditions, simple process, high economic benefit and suitability for large-scale production.
(2) The invention provides a synthesis method of 6-bromo-2-chloro-3-nitropyridine, which can solve the current situation that the price of 6-bromo-2-chloro-3-nitropyridine is high, and has a positive effect on the popularization of downstream products of 6-bromo-2-chloro-3-nitropyridine.
Drawings
FIG. 1 is a nuclear magnetic resonance diagram of 2-amino-3-nitro-6-bromopyridine.
FIG. 2 is a nuclear magnetic resonance diagram of 6-bromo-2-chloro-3-nitropyridine.
Detailed Description
The present invention will be described with reference to specific examples, which are not intended to limit the invention, but are merely illustrative of the invention so that the technical scheme of the invention can be more easily understood and grasped. The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available unless otherwise specified.
Example 1
1. Synthesis of 2-amino-3-nitro-6-bromopyridine
Into a 2L autoclave, 1L of a hydrobromic acid acetic acid solution having a mass concentration of 30% and 2-amino-3-nitro-6-chloropyridine (100 g,0.58 mol) were added, and the mixture was heated to 120℃and reacted for 12 hours. HPLC detection reaction is complete, decompression evaporation of acetic acid solution, pouring the residue into 1kg ice water, regulating pH to 8 with strong ammonia water, controlling temperature at 5-15 ℃, forming precipitate, filtering, washing with cold water; vacuum drying at 55deg.C to obtain yellow solid 123g of 2-amino-3-nitro-6-bromopyridine with yield of 98%, and nuclear magnetic resonance chart shown in figure 1.
1 H-NMR(400MHz,DMSO-d 6 )；δ:6.88(1H,m,J＝7.2Hz),8.24(1H,d,J＝8.4Hz),8.25(2H,br s)
2. Synthesis of 6-bromo-2-hydroxy-3-nitropyridine
Adding 5L of sulfuric acid with the mass concentration of 95% into a 10L reaction kettle, cooling to about 5 ℃, slowly adding 2-amino-3-nitro-6-bromopyridine (1000 g,4.59 mol), controlling the temperature to be not higher than 15 ℃, cooling to 0 ℃, and then slowly adding sodium nitrite (540 g,7.83mol dissolved in 1.2L of water) dropwise; controlling the temperature at 0-15 ℃, and stirring overnight at normal temperature. The next day, TLC showed the reaction was complete. Pouring the reaction solution into 12kg ice water, controlling the temperature not higher than 30 ℃, precipitating solid under stirring, filtering, washing with cold water, and drying; to give 854g of 6-bromo-2-hydroxy-3-nitropyridine as a yellowish green solid, yield y=85%.
3. Synthesis of 6-bromo-2-chloro-3-nitropyridine
1L three-mouth bottle, stirring, oil bath and condensing. 6-bromo-2-hydroxy-3-nitropyridine (50 g,0.23 mol), acetonitrile (600 mL) are added into a three-port bottle, the ice salt bath is cooled to 0 ℃, phosphorus pentachloride (50 g,0.24 mol) is slowly added dropwise under stirring, the temperature is controlled to be not higher than 5 ℃, after the addition, the reaction is kept at 0-5 ℃ for 1.5 hours, sampling is carried out, TLC detection reaction is complete, the reaction solution is poured into 1.5kg ice water for destruction, stirring is carried out for half an hour, the pH value of a saturated aqueous solution of sodium bicarbonate is adjusted to 7-8, the ethyl acetate is extracted three times (350 mL x 3), the organic phases are combined, the organic phases are washed twice with saturated salt water (500 mL x 2), anhydrous sodium sulfate (100 g) is dried, active carbon (3 g) is decolorized, filtration is carried out, ethyl acetate (100 mL) is concentrated to a small volume, solid precipitation is carried out, 1L petroleum ether is added, more solid precipitation is carried out, cooling is carried out to 0-5 ℃ for half an hour, the reaction solution is stirred for half an hour, filtration is carried out, and the reaction solution is dried, yellow solid 6-bromo-2-chloro-3-nitropyridine is obtained, the yield is 94% and is shown in a graph of FIG. 2.
1 H-NMR(400MHz,CDCl3-d 1 )；δ:7.64(1H,dd,J＝4.4Hz),8.11(1H,d,J＝8.4Hz)
Example 2
1. Synthesis of 2-amino-3-nitro-6-bromopyridine
To a 1L three-necked flask, a 30% strength by mass solution of hydrobromic acid in acetic acid (100 mL) was added, and 2-amino-6-chloro-3-nitropyridine (10 g) was slowly added at room temperature, and the reaction mixture was heated to 100 ℃. After 24 hours, 30% strength by mass aqueous hydrogen bromide in acetic acid (100 mL) was added. After 48 hours, the reaction mixture was cooled and concentrated. Pouring the residue into 0.5kg ice water, adjusting pH to 8 with strong ammonia water, controlling temperature at 5-15deg.C, forming precipitate, filtering, and washing with cold water; vacuum drying at 55 ℃ and recrystallization from isopropyl ether gave 9g of 2-amino-3-nitro-6-bromopyridine as a yellow solid in 72% yield.
2. Synthesis of 6-bromo-2-hydroxy-3-nitropyridine
Adding 5L of concentrated sulfuric acid into a 10L reaction kettle, cooling to about 5 ℃, slowly adding 2-amino-3-nitro-6-bromopyridine (1000 g,4.59 mol), controlling the temperature to be not higher than 15 ℃, cooling to 0 ℃, and then slowly adding sodium nitrite (700 g,10.14mol dissolved in 1.2L water) dropwise; controlling the temperature at 0-15 ℃, and stirring overnight at normal temperature. The next day, TLC showed the reaction was complete. Pouring the reaction solution into 12kg ice water, controlling the temperature not higher than 30 ℃, precipitating solid under stirring, filtering, washing with cold water, and drying; 834g of 6-bromo-2-hydroxy-3-nitropyridine was obtained as a yellowish green solid in a yield y=83%.
3. Synthesis of 6-bromo-2-chloro-3-nitropyridine
1L three-mouth bottle, stirring, oil bath and condensing. 6-bromo-2-hydroxy-3-nitropyridine (50 g,0.23 mol), acetonitrile (600 mL) were added to a three-necked flask, cooled to 0 ℃ in an ice-salt bath, phosphorus trichloride (33 g,0.24 mol) was slowly added dropwise with stirring, the temperature was controlled to be not higher than 5 ℃, the reaction was kept at 0-5 ℃ for 1.5 hours after the addition, sampling was carried out after the reaction was completed, TLC detection was completed, the reaction solution was poured into 1.2kg ice water for destruction, stirring was carried out for half an hour, a saturated aqueous solution of sodium hydrogencarbonate was adjusted to pH 7-8, ethyl acetate (350 mL 3) was extracted three times, the organic phase was combined, washed twice with saturated salt (500 mL 2) with water, dried over anhydrous sodium sulfate (100 g), activated carbon (3 g) was decolorized, filtered, ethyl acetate (100 mL) was concentrated to a small volume, solid was precipitated, 1L of petroleum ether was added, stirred for half an hour after cooling to 0-5 ℃ after the reaction was carried out, filtration, and oven-dried to obtain yellow solid 6-bromo-2-nitro-3-pyridine with yield=49 g.
Example 3
1. Synthesis of 2-amino-3-nitro-6-bromopyridine
To a 1L three-necked flask, a 30% strength by mass solution of hydrobromic acid in acetic acid (100 mL) was added, and 2-amino-6-chloro-3-nitropyridine (10 g) was slowly added at room temperature, and the reaction mixture was heated to 90 ℃. After 24 hours, 30% strength by mass aqueous hydrogen bromide in acetic acid (100 mL) was added. After 48 hours, the reaction mixture was cooled and concentrated. Pouring the residue into 0.5kg ice water, adjusting pH to 8 with strong ammonia water, controlling temperature at 5-15deg.C, forming precipitate, filtering, and washing with cold water; vacuum drying at 55 ℃ and recrystallization from isopropyl ether gave 8g of 2-amino-3-nitro-6-bromopyridine as a yellow solid in 64% yield.
2. Synthesis of 6-bromo-2-hydroxy-3-nitropyridine
Adding 5L of concentrated sulfuric acid into a 10L reaction kettle, cooling to about 5 ℃, slowly adding 2-amino-3-nitro-6-bromopyridine (1000 g,4.59 mol), controlling the temperature to be not higher than 15 ℃, cooling to 0 ℃, and then slowly adding sodium nitrite (348 g,5.04mol dissolved in 1.2L water) dropwise; controlling the temperature at 0-15 ℃, and stirring overnight at normal temperature. The next day, TLC showed the reaction was complete. Pouring the reaction solution into 12kg ice water, controlling the temperature not higher than 30 ℃, precipitating solid under stirring, filtering, washing with cold water, and drying; 804g of 6-bromo-2-hydroxy-3-nitropyridine were obtained as a yellowish green solid with a yield y=80%.
3. Synthesis of 6-bromo-2-chloro-3-nitropyridine
1L three-mouth bottle, stirring, oil bath and condensing. 6-bromo-2-hydroxy-3-nitropyridine (50 g,0.23 mol), toluene (600 mL) were added to a three-necked flask, the ice-salt bath was cooled to 0 ℃, phosphorus oxychloride (37 g,0.24 mol) was slowly added dropwise with stirring, the temperature was controlled to be not higher than 5 ℃, the reaction was kept at 0-5 ℃ for 1.5 hours after the addition, sampling was carried out after the reaction was completed, TLC detection was completed, the reaction solution was poured into 1.2kg ice water for destruction, stirring was carried out for half an hour, a saturated aqueous solution of sodium hydrogencarbonate was adjusted to pH 7-8, ethyl acetate (350 mL x 3) was extracted three times, the organic phase was combined, washed twice with saturated salt (500 mL x 2) with water, dried over anhydrous sodium sulfate (100 g), activated carbon (3 g) was decolorized, filtered, ethyl acetate (100 mL) was concentrated to a small volume, 1L petroleum ether was added, and more solid was precipitated, cooled to 0-5 ℃ for half an hour with stirring, and dried to obtain yellow solid 6-bromo-2-nitro-pyridine with yield=46 g.
The above detailed description is directed to a specific description of one possible embodiment of the invention, which is not intended to limit the scope of the invention. It should be noted that all equivalent implementations or modifications that do not depart from the spirit and scope of the present invention are intended to be included within the scope of the present invention. The scope of the invention should therefore be determined by the appended claims.
Claims (15)
1. A method for synthesizing 6-bromo-2-chloro-3-nitropyridine, comprising the steps of:
(1) 2-amino-3-nitro-6-chloropyridine reacts with acetic acid solution of hydrogen bromide to obtain 2-amino-3-nitro-6-bromopyridine;
(2) Diazotizing 2-amino-3-nitro-6-bromopyridine to obtain 6-bromo-2-hydroxy-3-nitropyridine;
(3) And reacting the 6-bromo-2-hydroxy-3-nitropyridine with a chlorinating agent to obtain 6-bromo-2-chloro-3-nitropyridine.
2. The synthesis method according to claim 1, wherein the step (1) is:
adding 2-amino-3-nitro-6-chloropyridine into hydrobromic acid acetic acid solution, heating until T1 is completely reacted under heat preservation, decompressing and evaporating the solution, pouring into ice water, adjusting pH, controlling the temperature to be T2, filtering, washing with water, and drying to obtain 2-amino-3-nitro-6-bromopyridine;
or adding 2-amino-3-nitro-6-chloropyridine into hydrobromic acid acetic acid solution, heating until T1 is completely reacted under heat preservation, decompressing and evaporating the solution, pouring into ice water, adjusting pH, controlling the temperature at T2, filtering, washing with water, drying, and recrystallizing to obtain 2-amino-3-nitro-6-bromopyridine.
3. The method of claim 2, wherein the temperature of T1 in step (1) is: 30-150 ℃; t2 is at a temperature of 0℃to 30 ℃.
4. A method according to claim 3, wherein the temperature of T1 in step (1) is: 90-120 ℃; t2 is at a temperature of 5-15 ℃.
5. The synthesis method according to claim 1, wherein the step (2) is: adding concentrated sulfuric acid into a reaction bottle, cooling to 5 ℃, adding the 2-amino-3-nitro-6-bromopyridine obtained in the step (1), controlling the temperature to be not higher than 15 ℃, adding sodium nitrite aqueous solution when the temperature is reduced to 0 ℃, controlling the temperature to be within the range of T3, stirring overnight at normal temperature, completely reacting, pouring the reaction solution into ice water, controlling the temperature to be not higher than 30 ℃, precipitating solid under stirring, filtering, washing with water, and drying to obtain the 6-bromo-2-hydroxy-3-nitropyridine.
6. The method according to claim 5, wherein the temperature of T3 in the step (2) is-10℃to 40 ℃.
7. The method of claim 6, wherein the temperature of T3 in step (2) is 0 ℃ to 15 ℃.
8. The method according to claim 5, wherein the molar ratio of 2-amino-3-nitro-6-bromopyridine to sodium nitrite in step (2) is 1:1-3.
9. The synthesis method according to claim 1, wherein the step (3) is to add a solvent into a reaction bottle, add the 6-bromo-2-hydroxy-3-nitropyridine obtained in the step (2) under stirring, cool the ice salt bath to 0 ℃, add a chlorinating agent under stirring, control the temperature to T4, keep the reaction at a temperature of completion, pour the reaction solution into ice water, stir, adjust the pH, extract and combine the organic phases, wash with water, dry, decolorize, filter, rinse, concentrate the organic phases to a small volume, precipitate solids, add petroleum ether, cool to 0-5 ℃, stir, filter, dry, obtain the 6-bromo-2-chloro-3-nitropyridine.
10. The method of claim 9, wherein the temperature of T4 in step (3) is-10 ℃ to 40 ℃.
11. The method of claim 10, wherein the temperature of T4 in step (3) is 0 ℃ to 5 ℃.
12. The method according to claim 9, wherein the solvent in the step (3) comprises ethyl acetate, 1, 4-dioxane, acetonitrile, N-dimethylformamide, toluene.
13. The method according to claim 9, wherein the chlorinating agent in step (3) comprises phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, bis (trichloromethyl) carbonate, trichloromethyl chloroformate.
14. Use of a synthetic method according to any one of claims 1 to 13, characterized in that it comprises use in the preparation of 6-bromo-2-chloro-3-nitropyridine or an analogue thereof, and a pharmaceutically acceptable carrier and/or excipient.
15. The use according to claim 14, wherein the analogue is a derivative of 6-bromo-2-chloro-3-nitropyridine, a pharmaceutically acceptable salt thereof, a tautomer thereof and/or a stereoisomer thereof.
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